1. Field of the Invention
The present invention relates to a novel process for preparing an aminostilbene derivative, which is important as an active component of anticancer drugs or an intermediate for preparation thereof. The present invention further provides a process for producing an aminostilbene derivative with an enhanced efficiency and industrial convenience as compared to the conventional techniques in the art.
2. Discussion of the Background
Combretastatins, including cis-stilbene as the basic skeleton, are provided with intensive mitosis inhibiting activity and intensive cytotoxicity. Therefore, investigations are on going for the development of anticancer drugs using a derivative thereof as the active (effective) component. In particular, development of an anticancer drug is now desired for the compounds represented by the following general formulas (3) or (4), since these compounds have low toxicity and high therapeutic efficacy (refer to: Japanese Patent Kokai Publications JP-A-7-228,558 and JP-A-8-301,831). 
In the above formulas (3) and (4), each of R1, R2 and R3 independently represents an alkyl group having 1-3 carbon atoms, X represents a hydrogen atom or a nitrile group, Y represents an alkoxy group having 1-3 carbon atoms, an alkyl group having 1-6 carbon atoms or a halogen atom and Z represents an amino acid acyl group, respectively.
The compounds represented by formulas (3) or (4) have an amino group or a substituted amino group on the benzene ring of phenyl group. A proposal has been set forth for a method of converting a nitro group into an amino group by reduction as a process for preparation these compounds, for example, the reducing method using zinc-acetic acid (refer to: Japanese Patent Kokai Publication JP-A-7-228,558) and the reducing method using sodium dithionite (Bioorganic and Medicinal Chemistry, vol. 8, 2000, page 2417). However, in the zinc-acetic acid method, it is necessary to use zinc in an extremely large excess based on the nitro compound, which is the substrate in the reaction. Consequently, a large amount of zinc is yielded as waste matter further accompanied with, e.g., exothermic decomposing property thereof so that there are many of problems in the environmental consideration and safety consideration for industrialization. In addition, in the sodium dithionite method, sodium dithionite in a large excess is used and the resultant yield is not sufficient.
It is desirable to adopt a stoichiometric reaction, or more desirably to adopt a catalytic reaction, for establishing a production process that yields reduced quantities of waste matter. However, it is not easy to selectively reduce only the nitro groups without any affect on the double bond under catalytic reduction conditions as it is usual for such a condition to induce reduction of the carbon-carbon double bonds to single bonds or cis-trans isomerization of carbon-carbon double bonds. In other words, although more exemplifications of the preparation of an aminostilbene derivative from a nitrostilbene derivative by the catalytic reaction that include little description on the stereochemistry of double bonds may be found, there are report articles on the hydrogenation method using a platinum oxide catalyst (refer to J. Am. Chem. Soc., 1940, vol. 62, page 1211), on the hydrogenation method using platinum on carbon (refer to Japanese Patent Kokai Publication JP-A-6-172,295), and so forth. The present inventors have confirmed that the object compound of the present invention is formed merely in a trace amount and the isomerization and reduction of the double bond are mainly induced with predominance so that these methods are industrially not useful (refer to after-mentioned Comparative Examples) when these methods are applied using the compound used as the starting material in the present invention.
Accordingly, there remains a critical need and a demand for a method of selectively converting the nitro group of the above nitrostilbene derivative into an amino group with high efficiency.